Morphinans are compounds based on the core chemical structure

A common example of a morphinan is morphine, a widely used and powerful analgesic. Morphine is an opioid that binds to opioid receptors in the central nervous system. However, the drug has serious side effects that present severe clinical problems, including drug dependence, suppression of respiration and suppression of smooth muscle movement. Alternative morphinan analogs have been studied and investigated in a search for compounds that shares the benefits of morphine with fewer negative side effects.
U.S. Pat. No. 4,218,454 to DeGraw et al. discloses morphinan analogs having the formula
wherein R is hydrogen or methyl and R′ is selected from various alkyl and alkene groups with a CH chiral moiety directly attached to N. The compounds are prepared using codeine as a starting material. In a typical synthesis, codeine is converted to norcodeine in two reaction steps. The norcodeine product is n-alkylated using lactonitrile, and the lactonitrile adduct is converted to the target morphinan analog in a two step procedure using first a Grignard reagent to transform a nitrile group to a cyclopropane group followed by diphenyphosphide to convert R from methyl to hydrogen. The compounds prepared using this method are reported to have strong agonist potency, moderate antagonist qualities, and low addiction potential.
U.S. Pat. No. 4,749,706 to Lawson et al. discloses morphinan analogs having the formula
wherein Y is OH or OMe; the dotted line indicates the presence or absence of a π bond; X is —OH or ═O. The absolute configuration of the α-carbon (i.e., the carbon attached to the nitrogen atom and the cyclopropane group) is not disclosed. The compounds are prepared using morphine as a starting material. In a typical synthesis, morphine is converted to normorphine in two reaction steps. The normorphine product is N-alkylated using sodium cyanoborohydride (NaCNBH3). The resulting mixture of diastereomers is reacted with benzoyl chloride to form the dibenzoate ester, and then separated using preparative HPLC. Removal of the benzoate esters affords the final product. The compounds prepared by this method are reported to be highly active analgesics and to have minimal addicting capability.
The synthetic methods described in the above-mentioned US patents involve numerous reaction steps and often produce low yields [<5%]. In addition, while the methods may be suitable for laboratory-scale preparations, scale-up of the methods for large-scale preparations is fraught with practical difficulties.
Beyond the US patents mentioned above, N-demethylations of morphine have been conducted utilizing toxic agents such as cyanogen bromide, ACE-Cl, and methyl chloroformate. These reagents lead to N—CN or N-carbamates which require various conditions which are laborious in their work-up. For example, the intermediate from treatment with ACE-Cl requires long periods of reflux with powder zinc metal
Previously, preparations of Buprenorphine and other orvinols were conducted including an N-demethylation step using methylazodicarboxylate as a mild oxidizing agent to convert the N-methyl to an aminal (see Bentley et al., (1967) Journal of the American Chemical Society, 89:13, 3281-3292). This method was reportedly not effective for opiates, having been tested on codeine and morphine.

Furthermore, published methods for N-alkylation of opioids are associated with a variety of difficulties. In the methods described in U.S. Pat. No. 4,749,706, NaCNBH3 must be added in portions over 1 hour and the pH must be adjusted by dropwise addition of HOAc during the reaction. The reaction mixture is heterogeneous slurry, requiring vigorous stirring.
The present invention is directed at addressing one or more of the abovementioned drawbacks.